There is no known therapy for Cerebral Amyloid Angiopathy (CAA), an important cause of hemorrhagic stroke and other clinical syndromes in the elderly. The pathologic basis of CAA-related stroke is deposition of the Amyloid B-peptide (AB) in cerebral vessels, and resultant degeneration of the vessel wall. We propose a multi-center, phase II pilot study of the safety, tolerability, and preliminary efficacy of NC-758 for secondary prevention of recurrent CAA-related intracerebral hemorrhage. NC-758 is a small molecule designed to compete with glycosaminoglycans for binding to AB. Preliminary studies have demonstrated that this compound penetrates to the CNS, inhibits AB fibril formation and AB-induced cellular toxicity, and reduces severity of CAA in a transgenic mouse model without evidence for major intrinsic toxicity. The proposed trial builds on progress by the Principal Investigator in the diagnosis and staging of CAA. Participants will be survivors of lobar hemorrhagic stroke, considered at high-risk for recurrence based on baseline gradient-echo MRI scan, or apolipoprotein-E genotype. An anticipated 280 patients will be screened at 20 participating sites, and 210 patients randomized to receive low-dose NC-758, high-dose NC-758, or placebo. Patients will be treated for a 16-month period, and followed for adverse clinical events, laboratory abnormalities, and recurrent stroke or decline in cognitive, functional, or neurologic status. At 8 and 16 months of treatment, subjects will undergo follow-up MRI scans to determine the appearance of new hemorrhagic lesions during treatment. The proposed sample size is calculated to have high likelihood of detecting major adverse effects associated with NC-758, and for detecting a 50% reduction in appearance of new symptomatic and asymptomatic hemorrhages. In addition to testing a promising agent for CAA, the proposed study will generate the organization and pilot data to serve as a springboard for future trials of emerging anti-amyloid treatments. [unreadable] [unreadable]